Letter pubs.acs.org/OrgLett
Selective Access to E- and Z‑ΔIle-Containing Peptides via a Stereospecific E2 Dehydration and an O → N Acyl Transfer Zhiwei Ma, Jintao Jiang, Shi Luo, Yu Cai, Joseph M. Cardon, Benjamin M. Kay, Daniel H. Ess,* and Steven L. Castle* Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, United States S Supporting Information *
ABSTRACT: A concise synthesis of peptides that contain E- or Zdehydroisoleucine (ΔIle) residues is reported. The key reaction is an unusual anti dehydration of β-tert-hydroxy amino acid derivatives that is mediated by the Martin sulfurane. A subsequent tandem Staudinger reduction−O → N acyl transfer process forges an amide bond to the ΔIle residue with minimal E/Z alkene isomerization. Density functional calculations attribute the stereospecific dehydration to a highly asynchronous E2 anti process. Scheme 1. Syntheses of ΔIle-Containing Peptides
α,β-Dehydroisoleucine (ΔIle) is present in several bioactive natural products including phomopsin A and yaku’amide A (Figure 1).1 E-ΔIle is more common than its Z-isomer, with
Figure 1. Representative natural products that contain ΔIle.
order to prevent generation of an azlactone that readily undergoes alkene isomerization.6,7 Herein, we report the incorporation of E- and Z-ΔIle into peptides without recourse to amide protection. Our strategy features an O → N acyl transfer reaction8 and relies on an unusual anti dehydration of tertiary alcohols that is mediated by the Martin sulfurane.9,10 Recently, we found that OsO4-catalyzed base-free aminohydroxylations11 can be conducted on trisubstituted alkenes with complete regioselectivity, affording rapid access to derivatives of β-tert-hydroxy amino acids.12 In the context of this study, we generated a ΔVal-containing peptide via dehydration of βOHVal. In an effort to extend this aminohydroxylation−
yaku’amides A and B1a representing the only natural products isolated to date that contain the latter residue. Bulky dehydroamino acids such as ΔIle are valued for their rigidifying effect on peptides2,3 and their increased stability to proteases relative to standard amino acids.4 Accordingly, new and efficient methods that facilitate their stereoselective incorporation into peptides are in demand. As part of synthetic efforts targeting the phomopsins, the Wandless5 and Joullié6 groups developed stereospecific dehydrations of β-hydroxyisoleucine (β-OHIle) derivatives for constructing E-ΔIle (Scheme 1). In the course of preparing yaku’amide A, Inoue et al. devised a different strategy for accessing E- and Z-ΔIle featuring a Cu-catalyzed coupling reaction.7 Unfortunately, in each case peptide coupling of the Cterminal ΔIle requires protection of the neighboring amide in © 2014 American Chemical Society
Received: June 30, 2014 Published: July 16, 2014 4044
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dehydration strategy to the construction of ΔIle derivatives, we examined the aminohydroxylation of E-enoate 13 (Scheme 2).
demonstrating the impact of subtle structural differences on the reactivity of these compounds. We next attempted to perform the aminohydroxylation on a substrate possessing an activated carboxylate group that could be employed directly in a subsequent amidation. Although the phenyl ester21 analogous to 17 was a viable aminohydroxylation substrate, problems with the deprotection and coupling steps caused us to abandon this approach. Attempted dehydrations of tripeptides with a β-hydroxy amino acid as the central residue did not proceed, demonstrating the necessity of performing the dehydration prior to amidation. At this stage, we were drawn to O → N acyl transfer chemistry8 as a means of precluding alkene isomerization without resorting to protection of the neighboring backbone amide. We envisioned that β-azidoethyl esters could be stereoselectively dehydrated and then converted into amides via a tandem reduction/ rearrangement process. The requisite substrates were constructed via saponification of ester 15 followed by alkylation with iodides 21a and 21b (Scheme 3).22 Alkylative esterification was
Scheme 2. Synthesis and anti Dehydration of 15 and 19
Scheme 3. Stereoselective Synthesis of Z-ΔIle-Containing Peptides 24a and 24ba This alkene reacted sluggishly when CbzHN−OC(O)p-ClPh11 was employed as the nitrogen source reagent, and copious quantities of benzyl carbamate (CbzNH2) were obtained. Inspired by the work of Donohoe et al. on tethered aminohydroxylations,13 we reasoned that a less basic leaving group on the carbamate would improve the reaction. Indeed, CbzHN− OMs gave significantly better results, as racemic β-OHIle derivative 14 was produced in good yield (70%) along with smaller amounts of CbzNH2 byproduct. While this work was in progress, the virtues of sulfonyloxycarbamates as reagents for base-free aminohydroxylations were noted by McLeod et al.14 Hydrogenolysis of 14 and coupling of the resulting free amine to Cbz-Gly afforded dipeptide 15. Since dehydrations of tertiary alcohols with the Martin sulfurane are reported to proceed via E1-like mechanisms,9,15 we were not expecting this reagent to dehydrate 15 stereoselectively. We were therefore surprised to find that exposure of 15 to the Martin sulfurane furnished ZΔIle-containing dipeptide 16 as the product of clean anti dehydration. No minor isomers were visible by 1H NMR. While anti-selective or E2-like dehydrations of tertiary alcohols promoted by this reagent are not unprecedented,16 they are much less common than E1-like dehydrations of these substrates. In our hands, application of the Wandless protocol to 15 delivered 16 with varying levels of selectivity (4−8:1 dr), so we continued our studies with the Martin sulfurane as our reagent of choice.17 Importantly, we were able to establish the stereospecific nature of this process by applying the four-step sequence developed with E-enoate 13 to Z-enoate 17 (Scheme 2). The dehydration of dipeptide 19 produced E-ΔIle-containing peptide 20 as a single detectable isomer. Since standard peptide couplings would scramble the alkene stereochemistry in the absence of amide protection, we considered other strategies (e.g., Staudinger ligations,18 thioacid−based couplings,19 and B(OCH2CF3)320) for elaborating 16. In preparation for evaluating these methods, we hydrolyzed the ethyl ester of 16. Surprisingly, saponification was sluggish and accompanied by alkene isomerization (ca. 2:1 dr). Presumably, the hindered nature of the ester moiety allows enolization via γdeprotonation to compete with saponification, thereby enabling isomerization. In contrast, Shangguan and Joullié reported the isomerization-free saponification of a related ΔIle-derived ester,6
a
Asterisks on adjacent atoms indicate the portrayal of relative stereochemistry. b The conversion of 23b into 24b was conducted with piperidine instead of morpholine as the base.
necessary to avoid nonselective dehydration that would occur under typical conditions (i.e., DCC), and iodides 21a and 21b were selected to serve as surrogates for the simplest (Gly) and bulkiest (Val) amino acids that are coupled to the C-termini of ΔIle residues in yaku’amide A. Esters 22a and 22b were produced in good yields, with the latter generated as an inconsequential mixture of diastereomers due to the racemic nature of 15. Pleasingly, the esters underwent stereoconvergent anti dehydration when exposed to the Martin sulfurane, furnishing Z-ΔIle derivatives 23a and 23b as single isomers. Dehydration of 22a was clean at 0 °C, whereas a small amount of E-isomer was obtained when the bulkier 22b was dehydrated at 0 °C (ca. 7:1 dr). Fortunately, only the desired Z-23b was observed when the reaction was maintained at −20 °C. Staudinger reduction of azides 23a and 23b was facile, and addition of an amine base to the mixture upon completion of the reduction triggered O → N acyl transfer, producing amides 24a and 24b in good yields. Minor amounts of alkene isomerization occurred during this process (≥10:1 dr), but to our knowledge these are the best results to date for amidations of ΔIle derivatives in the absence of backbone amide protecting groups. This anti dehydration−O → N acyl transfer strategy worked equally well for the production of E-ΔIle-containing peptides (Scheme 4). Dehydrations of esters 25a and 25b were conducted at the same temperatures as the corresponding reactions in the Z-series, and isomerically pure 4045
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(CF 3 ) 2 CHO − anion. Without this hydrogen bond the carbocation is endergonic by >50 kcal/mol. These thermodynamics provide strong evidence against an E1 dehydration mechanism. We then searched for possible E2 and E1cb transition states from 32. TS1-anti (Figure 2) is the lowest-energy transition
Scheme 4. Stereoselective Synthesis of E-ΔIle-Containing Peptides 27a and 27ba
a
Asterisks on adjacent atoms indicate the portrayal of relative stereochemistry. b The conversion of 26b into 27b was conducted in DMF−H2O instead of THF−H2O.
alkenes were obtained. The reduction and rearrangement of esters 26a and 26b proceeded without incident, delivering the targeted amides in excellent yields with minimal E-to-Z isomerization (≥10:1 dr). The high stereoselectivity facilitated by the Martin sulfurane was unexpected since earlier reports have proposed that tertiary alcohols may undergo elimination via an E1-like mechanism.9,15 However, at least one study suggests the feasibility of an E2-type dehydration.16 This prompted us to employ density functional calculations (Gaussian 09)23 to examine E1, E2, and E1cb pathways for our anti dehydration using alcohol 28 (Scheme 5,
Figure 2. M06-2X anti and syn E2 transition states (distances reported in Å; phenyl groups partially obscured for clarity).
state, with ΔG‡ = 13.9 kcal/mol. Inspection of TS1-anti indicates that it is either a highly asynchronous E2 transition state or an E1cb transition state. The nascent partial O1−H bond (1.26 Å) and the breaking C1−H bond (1.34 Å) are both highly advanced, while the C2−O bond (1.53 Å) is only stretched by 0.03 Å. While normal-mode vibrational analysis for TS1-anti did not show significant motion in the C2−O bond, IRC calculations suggest that TS1-anti connects to alkene 30 with no intermediate. We were unable to locate an E1cb transition state, and mapping of the entire potential energy landscape showed only TS1-anti and no local minimum for a carbanion intermediate. This suggests that TS1-anti is best interpreted as a highly asynchronous E2 transition state. A similar transition state was found by Itoh and Yamataka for the elimination reactions of 2-aryl-3-chloro-2propanols.27 We also considered that TS1-anti might be a merged transition state for E2 and E1cb pathways that could dynamically branch to alkene 30 and a carbanion.28 We have discounted this possibility for two reasons. First, attempts to optimize a carbanion intermediate resulted in the formation of 30 and ejection of the OSPh2 leaving group. Second, Itoh and Yamataka have shown that if the IRC follows an asynchronous E2 pathway, then all dynamics trajectories show only E2 products and no reaction pathway branching. The observed stereoselectivity is likely the result of an anti transition state that is lower in energy than any of the possible syn transition states. Figure 2 shows the lowest-energy syn transition state that was located (TS1-syn). It is not completely eclipsed and exhibits a moderate twist with a H−C1−C2−O2 dihedral angle of ∼46°. The ΔG‡ for TS1-syn is 16.6 kcal/mol, which is 2.7 kcal/mol higher in free energy than TS1-anti and qualitatively in accordance with the high stereoselectivity reported in Scheme 2 for the dehydration of 15. In summary, we have developed a concise and efficient route to E- and Z-ΔIle-containing peptides featuring an anti-selective dehydration of β-OHIle derivatives and a tandem Staudinger reduction/O → N acyl transfer. The former reaction is a rare example of a Martin sulfurane mediated tertiary alcohol dehydration that proceeds by a concerted asynchronous E2 mechanism. The latter process furnishes E- and Z-ΔIle-derived amides without recourse to backbone amide protection. It is
Scheme 5. M06-2X/6-31+G(d,p) [CHCl3, SMD Solvent] Energies for Dehydration (kcal/mol)
a model of substrate 15) and sulfurane 29 (a slightly simplified version of the Martin sulfurane). M06-2X/6-31+G(d,p) theory24 was selected since it provides accurate E2 transition state barriers.25 Geometry optimizations and normal-mode frequency analysis were carried out in CHCl3 using the SMD implicit solvent model.26 The reaction of 28 with sulfurane 29 creates an equivalent of (CF3)2CHOH and intermediate 31, which is endergonic by 4.4 kcal/mol. Subsequent loss of the alkoxide (CF 3) 2CHO − generates the −OSPh2 leaving group. Complete dissociation of (CF3)2CHO− requires 22.5 kcal/mol of free energy, so it is possible that this anion does not actually leave the solvation sphere of 31. Indeed, structure 32 contains a hydrogen bond between the alkoxide and the amide. Intermediate 32, the key species from which the E1, E2, and E1cb pathways diverge, is endergonic by 9.2 kcal/mol. The E1 pathway, which involves loss of OSPh2 to form carbocation 33, requires 26.6 kcal/mol of free energy. This cation retains its hydrogen bond to the 4046
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Spampinato, S.; Civera, M.; Juaristi, E.; Escudero, M. Eur. J. Med. Chem. 2013, 66, 258. (3) For a review, see: Bonauer, C.; Walenzyk, T.; König, B. Synthesis 2006, 1. (4) (a) English, M. L.; Stammer, C. H. Biochem. Biophys. Res. Commun. 1978, 83, 1464. (b) English, M. L.; Stammer, C. H. Biochem. Biophys. Res. Commun. 1978, 85, 780. (c) Shimohigashi, Y.; Stammer, C. H. J. Chem. Soc., Perkin Trans. 1 1983, 803. (5) (a) Stohlmeyer, M. M.; Tanaka, H.; Wandless, T. J. J. Am. Chem. Soc. 1999, 121, 6100. (b) Grimley, J. S.; Sawayama, A. M.; Tanaka, H.; Stohlmeyer, M. M.; Woiwode, T. F.; Wandless, T. J. Angew. Chem., Int. Ed. 2007, 46, 8157. (6) Shangguan, N.; Joullié, M. Tetrahedron Lett. 2009, 50, 6748. (7) Kuranaga, T.; Sesoko, Y.; Sakata, K.; Maeda, N.; Hayata, A.; Inoue, M. J. Am. Chem. Soc. 2013, 135, 5467. (8) (a) Tamamura, H.; Hori, T.; Otaka, A.; Fujii, N. J. Chem. Soc., Perkin Trans. 1 2002, 577. (b) Yoshiya, T.; Kawashima, H.; Sohma, Y.; Kimura, Y.; Kiso, Y. Org. Biomol. Chem. 2009, 7, 2894. (c) Tailhades, J.; Gidel, M.-A.; Grossi, B.; Lécaillon, J.; Brunel, L.; Subra, G.; Martinez, J.; Amblard, M. Angew. Chem., Int. Ed. 2010, 49, 117. (9) (a) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327. (b) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003. (10) For anti dehydrations of secondary alcohols (i.e., Thr and βOHPhe), see: Ferreira, P. M. T.; Maia, H. L. S.; Monteiro, L. S. Tetrahedron Lett. 1998, 39, 9575. (11) Harris, L.; Mee, S. P. H.; Furneaux, R. H.; Gainsford, G. J.; Luxenburger, A. J. Org. Chem. 2011, 76, 358. (12) Ma, Z.; Naylor, B. C.; Loertscher, B. M.; Hafen, D. D.; Li, J. M.; Castle, S. L. J. Org. Chem. 2012, 77, 1208. (13) Donohoe, T. J.; Bataille, C. J. R.; Gattrell, W.; Kloesges, J.; Rossignol, E. Org. Lett. 2007, 9, 1725. (14) Masuri; Willis, A. C.; McLeod, M. D. J. Org. Chem. 2012, 77, 8480. (15) (a) Sparling, B. A.; Moslin, R. M.; Jamison, T. F. Org. Lett. 2008, 10, 1291. (b) Wang, Z. Comprehensive Organic Name Reactions and Reagents; Wiley: Hoboken, NJ, 2010; pp 1841−1844. (16) Kok, S. H.-L.; Lee, C. C.; Shing, T. K. M. J. Org. Chem. 2001, 66, 7184. (17) In our earlier studies, low yields of ΔVal-containing products were obtained via the Cu(OTf)2−EDC protocol. Accordingly, this method was not explored for the dehydration of 15. (18) (a) Soellner, M. B.; Tam, A.; Raines, R. T. J. Org. Chem. 2006, 71, 9824. (b) Kosal, A. D.; Wilson, E. E.; Ashfeld, B. L. Chem.Eur. J. 2012, 18, 14444. (19) (a) Crich, D.; Sana, K.; Guo, S. Org. Lett. 2007, 9, 4423. (b) Chen, W.; Shao, J.; Hu, M.; Yu, W.; Giulianotti, M. A.; Houghten, R. A.; Yu, Y. Chem. Sci. 2013, 4, 970. (20) Lanigan, R. M.; Starkov, P.; Sheppard, T. D. J. Org. Chem. 2013, 78, 4512. (21) Fang, G.-M.; Cui, H.-K.; Zheng, J.-S.; Liu, L. ChemBioChem 2010, 11, 1061. (22) Details of the synthesis of 21a and 21b are found in the Supporting Information. (23) Frisch, M. J., et al. Gaussian 09, revision B.01; Gaussian, Inc.: Wallingford, CT, 2009. (24) (a) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215. (b) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157. (25) Swart, M.; Solà, M.; Bickelhaupt, F. M. J. Chem. Theory Comput. 2010, 6, 3145. (26) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378. (27) Itoh, S.; Yamataka, H. Chem.Eur. J. 2011, 17, 1230. (28) Ess, D. H.; Wheeler, S. E.; Iafe, R. G.; Xu, L.; Celebi-Olcum, N.; Houk, K. N. Angew. Chem., Int. Ed. 2008, 47, 7592.
anticipated that oxidation of the primary alcohols present in 24 and 27 will enable elongation of the peptide chains. The dehydration substrates are rapidly prepared via regioselective aminohydroxylation of trisubstituted alkenes. The stereoconvergent nature of the dehydration (i.e., the two diastereomers of 22b and 25b are converted into single alkene products) allows the use of a racemic aminohydroxylation. Density functional calculations indicate that the excellent stereoselectivity of the dehydration can be attributed to a highly asynchronous E2 anti pathway in which deprotonation is significantly more advanced at the transition state than C−O bond cleavage. This pathway is considerably lower in energy than all others that were examined (i.e., E2 syn, E1). Although no E1cb transition state was located, it is likely that the electron-withdrawing carboxylate group of the substrates is at least partially responsible for stabilizing the E2 anti transition state. This suggests that tertiary alcohols with vicinal electron-withdrawing groups might be good substrates for anti-selective dehydrations mediated by the Martin sulfurane. Due to the importance of ΔIle1 and related bulky dehydroamino acids,2−4 we envision many future applications of this strategy.
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ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures, characterization data, and NMR spectra for all new compounds, as well as descriptions of computational methods. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank Brigham Young University (Graduate Studies and Bradshaw Fellowships to Z.M., Cancer Research Center Fellowships to J.J. and Y.C., Undergraduate Research Awards to S.L. and J.M.C., CHIRP Award to S.L.C.) for support. We also thank Prof. Jeremy May (University of Houston) for helpful discussions.
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REFERENCES
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